4-(azacycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and in cosmetics

ABSTRACT

4-(Azacycloalkyl)benzene-1,3-diol compounds are described corresponding to general formula (I) below: 
     
       
         
         
             
             
         
       
     
     Also described, are compositions including the same, processes for preparation thereof and uses thereof in pharmaceutical or cosmetic compositions to treat pigmentary disorders.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of copending U.S. patent applicationSer. No. 14/200,954, filed Mar. 7, 2014, which is a continuation of U.S.patent application Ser. No. 13/611,546, filed Sep. 12, 2012, now U.S.Pat. No. 8,697,726, which is a continuation of U.S. patent applicationSer. No. 13/131,363, filed Sep. 12, 2011, now U.S. Pat. No. 8,299,259,which is a National Stage of PCT/EP2009/066268, filed Dec. 2, 2009, anddesignating the United States (published in the English language on Jun.10, 2010 as WO 2010/063774 A1; the title and abstract were alsopublished in English), which claims benefit of U.S. Provisional PatentApplication No. 61/193,460, filed Dec. 2, 2008 and also claims priorityunder 35 U.S.C. §119 to French Patent Application No. 0858207, filedDec. 2, 2008, each of the earlier applications being hereby expresslyincorporated by reference in their entirety and each assigned to theassignee hereof.

The invention relates to novel 4-(azacycloalkyl)benzene-1,3-diolcompounds as industrial and useful products. It also relates to theprocess for the preparation thereof and to the use thereof, astyrosinase inhibitors, in pharmaceutical or cosmetic compositions foruse in the treatment or prevention of pigmentary disorders.

Skin pigmentation, in particular human skin pigmentation, is the resultof melanin synthesis by dendritic cells, melanocytes. Melanocytescontain organelles called melanosomes which transfer melanin into theupper layers of keratinocytes which are then transported to the surfaceof the skin through differentiation of the epidermis (Gilchrest B A,Park H Y, Eller M S, Yaar M, Mechanisms of ultraviolet light-inducedpigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing V J, TsukamotoK, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5:2902-2909).

Among the enzymes of melanogenesis, tyrosinase is a key enzyme whichcatalyses the first two steps of melanin synthesis. Homozygous mutationsof tyrosinase cause oculocutaneous albinism type I characterized by acomplete lack of melanin synthesis (Toyofuku K, Wada I, Spritz R A,Hearing V J, The molecular basis of oculocutaneous albinism type 1(OCA1): sorting failure and degradation of mutant tyrosinases results ina lack of pigmentation. Biochem J 2001; 355: 259-269).

In order to treat pigmentation disorders resulting from an increase inmelanin production, for which there is no treatment that meets all theexpectations of patients and dermatologists, it is important to developnew therapeutic approaches.

Most of the skin-lightening compounds that are already known are phenolsor hydroquinone derivatives. These compounds inhibit tyrosinase, but themajority of them are cytotoxic to melanocytes owing to the formation ofquinones. There is a risk of this toxic effect causing a permanentdepigmentation of the skin. The obtaining of compounds that can inhibitmelanogenesis while at the same time being very weakly cytotoxic ordevoid of toxicity to melanocytes is most particularly sought.

Among the compounds already described in the literature, patentapplication WO 99/15148 discloses the use of 4-cycloalkyl resorcinols asdepigmenting agents.

Patent FR2704428 discloses the use of 4-haloresorcinols as depigmentingagents.

Patent applications WO 2006/097224 and WO 2006/097223 disclose the useof 4-cycloalkylmethyl resorcinols as depigmenting agents.

Patent application WO 2005/085169 discloses the use of alkyl3-(2,4-dihydroxyphenyl)propionate as a depigmenting agent.

Patent application WO 2004/017936 discloses the use of3-(2,4-dihydroxyphenyl)acrylamide as a depigmenting agent.

Patent application WO 2004/052330 discloses the use of4-[1,3]dithian-2-ylresorcinols as depigmenting agents.

More particularly, patent EP0341664 discloses the use of 4-alkylresorcinols as depigmenting agents, among which 4-n-butyl resorcinol,also known as rucinol, is part of the composition of a depigmentingcream sold under the name Iklen®.

The applicant has now discovered, unexpectedly and surprisingly, thatnovel compounds of 4-(azacycloalkyl)benzene-1,3-diol structure have avery good tyrosinase enzyme-inhibiting activity and a very lowcytotoxicity. Furthermore, these compounds have a tyrosinaseenzyme-inhibiting activity that is greater than that of rucinol while atthe same time being less cytotoxic with respect to melanocytes thanrucinol.

These compounds find uses in human medicine, in particular indermatology, and in the cosmetics field.

Thus, the present invention relates to the compounds of general formula(I) below:

in which:R1 represents:

a C₁-C₅ alkyl radical,

a C₃-C₆ cycloalkyl radical,

an aryl radical,

a substituted aryl radical,

an aralkyl radical,

a C₁-C₅ alkoxy radical,

an amino radical corresponding to structure (a):

in which R2 represents:

-   -   a hydrogen,    -   a C₁-C₅ alkyl radical,    -   a C₃-C₆ cycloalkyl radical,    -   an aryl radical,    -   a substituted aryl radical,    -   a pyridyl radical.    -   an aralkyl radical,    -   a radical corresponding to structure (b):

in which p can have the value 1 or 2,

-   -   a radical corresponding to structure (c):

in which R4 represents:

-   -   a carboxymethyl —COOCH₃ or carboxyethyl —COOEt radical,    -   a C₁-C₃ alkyl radical,    -   a hydrogen,

and R5 represents:

-   -   a substituted or unsubstituted aryl radical,    -   a C₃-C₆ cycloalkyl radical,    -   a pyridyl,

and R3 represents:

-   -   a hydrogen,    -   a C₁-C₅ alkyl radical;

R1 may also represent a radical corresponding to formula (d):

in which R6 represents:

-   -   a hydrogen,    -   a C₁-C₅ alkyl radical,    -   a C₃-C₆ cycloalkyl radical,    -   an aryl radical,    -   a substituted aryl radical.    -   a pyridyl radical.    -   an aralkyl radical,

R7 represents:

-   -   a hydrogen,    -   a C₁-C₅ alkyl radical,

and R8 represents:

-   -   a hydrogen,    -   a hydroxyl,    -   an amino radical,    -   a C₁-C₃ alkoxy radical:        Y represents a hydrogen or a fluorine, and        m and n can have the value 0, 1 or 2,        and also the salts of the compounds of formula (I), and the        isomer and enantiomer forms thereof.

Among the salts of the compounds of general formula (I) with apharmaceutically acceptable base, mention may preferably be made of thesalts with an organic base or with an inorganic base.

The suitable inorganic bases are, for example, potassium hydroxide,sodium hydroxide or calcium hydroxide.

The suitable organic bases are, for example, morpholine, piperazine orlysine.

The compounds of general formula (I) may also exist in the form ofhydrates or of solvates.

The solvents that are suitable for forming solvates are, for example,alcohols such as ethanol or isopropanol.

According to the present invention, the term “C₁-C₅ alkyl” denotes alinear or branched, saturated hydrocarbon-based chain containing from 1to 5 carbon atoms.

According to the present invention, the term “C₁-C₃ alkyl” denotes alinear or branched, saturated hydrocarbon-based chain containing from 1to 3 carbon atoms.

According to the present invention, the term “C₃-C₆ cycloalkyl” denotesa cyclic, saturated hydrocarbon-based chain containing from 3 to 6carbon atoms.

According to the present invention, the term “aryl” denotes a phenyl ora naphthyl.

According to the present invention, the term “substituted aryl” denotesa phenyl or a naphthyl substituted with one or more groups of atomschosen from an alkyl, an alkoxy, a fluorine and a trifluoromethyl.

According to the present invention, the term “aralkyl” denotes a C₁-C₅alkyl radical as defined above and substituted with a substituted orunsubstituted aryl radical.

According to the present invention, the term “C₁-C₅ alkoxy” denotes anoxygen atom substituted with a linear or branched, saturatedhydrocarbon-based chain containing from 1 to 5 carbon atoms.

According to the present invention, the term “C₁-C₃ alkoxy” denotes anoxygen atom substituted with a linear or branched, saturatedhydrocarbon-based chain containing from 1 to 3 carbon atoms.

According to the present invention, the compounds of general formula (I)that are particularly preferred are those for which:

R1 represents an aralkyl radical or an amino radical corresponding tostructure (a):

in which R2 represents:

-   -   a C₁-C₅ alkyl radical,    -   an aralkyl radical or    -   a radical corresponding to structure (d):

in which R4 represents:

-   -   a carboxymethyl —COOCH₃ or carboxyethyl —COOEt radical,    -   a C₁-C₃ alkyl radical,

and R5 represents:

-   -   a substituted or unsubstituted aryl radical,

and R3 represents a hydrogen,

Y represents a hydrogen atom or a fluorine,

m=1 and n=1,

and also the salts of these compounds of general formula (I), and theisomer and enantiomer forms thereof.

Among the compounds of formula (I) which are part of the context of thepresent invention, mention may in particular be made of the following:

-   1: 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl    ester-   2: [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone-   3: 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid pentylamide-   4: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl    ester-   5: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutyl    ester-   6: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid    cyclohexylamide-   7: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid phenylamide-   8: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid    (4-fluorophenyl)amide-   9: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid    (4-trifluoromethylphenyl)amide-   10: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester-   11: [4-(2,4-dihydroxyphenyl)piperidin-1-yl]phenylmethanone-   12: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid butylamide-   13: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid propylamide-   14: 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]butan-1-one-   15: 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-methylpropan-1-one-   16: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid phenylamide-   17: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (4-fluorophenyl)amide-   18: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid p-tolylamide-   19: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    phenethylamide-   20: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (3-fluorophenyl)amide-   21: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((R)-1-phenylethyl)amide-   22: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    methylphenylamide-   23: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    pyridin-2-ylamide-   24: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-phenylethyl)amide-   25: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-phenylpropyl)amide-   26:    (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one-   27: 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one-   28: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    2-fluorobenzylamide-   29: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    3-fluorobenzylamide-   30: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    4-fluorobenzylamide-   31: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid benzylamide-   32: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    2-methylbenzylamide-   33: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    3-methylbenzylamide-   34: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    4-methylbenzylamide-   35: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    2-methoxybenzylamide-   36: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    3-methoxybenzylamide-   37: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    4-methoxybenzylamide-   38: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-p-tolylethyl)amide-   39: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    [(S)-1-(4-fluorophenyl)ethyl]amide-   40: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (S)-indan-1-ylamide-   41: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-naphthalen-1-ylethyl)amide-   42: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-naphthalen-2-ylethyl)amide-   43: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    [(S)-1-(4-methoxyphenyl)ethyl]amide-   44: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    [(S)-1-(3-methoxyphenyl)ethyl]amide-   45:    (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one-   46: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-phenylethyl)amide-   47:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone-   48:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone-   49:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-one-   50:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-one-   51:    (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-fluorophenyl)ethanone-   52:    (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylethanone-   53:    (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylethanone-   54:    (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-trifluoromethylphenyl)ethanone-   55:    2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylbutan-1-one-   56:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-methoxy-2-phenylethanone-   57: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-cyclohexylethyl)amide-   58: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (1,2,3,4-tetrahydronaphthalen-1-yl)amide-   59:    (R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic    acid methyl ester-   60: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (pyridin-3-ylmethyl)amide-   61: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (pyridin-4-ylmethyl)amide-   62: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    benzylamide-   63: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    butylamide-   64: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (3-fluorophenyl)amide-   65: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    phenethylamide-   66:    (R)-{[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic    acid methyl ester-   67: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (S)-indan-1-ylamide-   68: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    [(S)-1-(4-methoxyphenyl)ethyl]amide-   69: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((S)-1-cyclohexylethyl)amide-   70:    (R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone-   71:    (S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone-   72:    (R)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylethanone-   73:    (S)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylethanone-   74:    (R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylpropan-1-one-   75:    (S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylpropan-1-one-   76:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylpropan-1-one-   77:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylpropan-1-one-   78:    (R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-fluorophenyl)acetic    acid methyl ester-   79:    (S)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-fluorophenyl)acetic    acid methyl ester-   80:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-methyl-3-phenylpropan-1-one-   81:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-methyl-3-phenylpropan-1-one-   82: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (pyridin-3-ylmethyl)amide-   83: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (pyridin-4-ylmethyl)amide-   84: (5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    ((R)-1-phenylethyl)amide-   85:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylbutan-1-one-   86:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylbutan-1-one-   87:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-fluorophenyl)-2-hydroxyethanone-   88:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-fluorophenyl)-2-hydroxyethanone-   89:    (S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-(3-methoxyphenyl)ethanone-   90:    (R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-(3-methoxyphenyl)ethanone.-   91: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    cyclohexylmethylamide-   92: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    cyclohexylmethylamide-   93: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2-ethylbutyl)amide-   94: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2-ethylbutyl)amide-   95: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    cyclopentylmethylamide-   96: 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    cyclopentylmethylamide-   97: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (6-methylpyridin-3-ylmethyl)amide-   98: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (4-methylpyridin-3-ylmethyl)amide-   99: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (5-methylpyridin-3-ylmethyl)amide-   100: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2-methylpyridin-3-ylmethyl)amide-   101: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2,6-dimethylpyridin-4-ylmethyl)amide-   102: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2-pyridin-2-ylethyl)amide-   103: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2-pyridin-3-ylethyl)amide-   104: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid    (2-pyridin-4-ylethyl)amide

The compounds of general formula (I) are prepared according to thegeneral reaction scheme shown in FIG. 1.

The compounds 2,4-bis(benzyloxy)bromobenzene (X=Br; Y=H) or1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene (X=I; Y=F) (1), which arecommercially available or prepared according to conventional synthesismethods (W. D. Langley, Org. Synth. I, 122 (1932)) (in the case of thefluoro compounds, Mottram, L. F.; Boonyarattanakalin, S.; Kovel, R. E.;Peterson, B. R. Organic Letters 2006, 8(4), 581-584) react in thepresence of butyllithium, for example, with azacycloalkanones (2) whichare commercially available or prepared according to conventionalsynthesis methods (W. D. Langley, Org. Synth. I, 122 (1932)) so as togive the corresponding benzyl alcohols of general formula (3) in whichY=H or F and Z=ethyl or tert-butyl (Annoura, H.; Nakanishi, K.; Uesugi,M.; Fukunaga, A.; Imajo, S.; Miyajima, A.; Tamura-Horikawa, Y.; Tamura,S.; Bioorg Med Chem 2002. 10 (2), 371-383).

The compounds of general formula (4) are obtained by hydrogenation ofthe benzyl alcohols of general formula (3) in the presence of hydrogenand of a palladium-based catalyst such as palladium-on-charcoal, forexample, in a solvent such as methanol (Merschaert, A.; Delhaye, L.;Kestemont, J.-P.; Brione, W.; Delbeke, P.; Mancuso, V.; Napora, F.;Diker, K.; Giraud, D.; Vanmarsenille, M.; Tetrahedron Lett 2003, 44(24). 4531-4534).

The compounds of general formula (4) may be benzylated using benzylbromide and a base such as potassium carbonate, for example, in asolvent such as methyl ethyl ketone, for example, in order to give thecompounds of general formula (5) (Bolek, D.; Guetschow, M.; J HeterocyclChem 2005, 42 (7), 1399-1403).

The compounds of general formula (5) are converted to amines of generalformula (6) through the action of trifluoroacetic acid, for example, ifZ=tert-butyl (Kasyan, A.; Wagner, C.; Maier, M. E.; Tetrahedron 1998, 54(28), 8047-8054) or else through the action of an aqueous solution ofpotassium hydroxide, for example, if Z=ethyl (Morice, C.; Domostoj, M.;Briner, K.; Mann, A.; Suffert, J.; Wermuth, C.-G.; Tetrahedron Lett2001, 42 (37), 6499-6502).

The compounds of general formula (6) are subsequently converted tocompounds of general formula (7).

The compounds of general formula (7) may:

-   -   either be ureas: they are obtained by reacting the compounds of        general formula (6) with isocyanates, for example (Ranise, A.;        Schenone, S.; Bruno, O.; Bondavalli, F.; Filippelli, W.;        Falcone, G.; Rivaldi, B.; Farmaco 2001, 56 (9), 647-657);    -   or be amides; they are obtained by reacting the compounds of        general formula (6) with acyl chlorides, for example        (Katritzky, A. R.; Singh, S. K.; Cai, C.; Bobrov, S.; J Org Chem        2006, 71 (9), 3364-3374) or with acids (De Laszlo, S. E.;        Allen. E. E.; Li, B.; Ondeyka. D.; Rivero, R.; Malkowitz, L.;        Molineaux, C.; Siciliano, S. J.; Springer, M. S.; Greenlee, W.        J.; Mantlo, N.; Bioorg Med Chem Lett 1997, 7 (2), 213-218);    -   or be carbamates: they are obtained by reacting the compounds of        general formula (6) with chloroformates, for example        (Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen, F.        J.; Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.;        Verghese, M.; Feldman, P. L.; J Med Chem 1995, 38 (24),        4848-4854).

The compounds of general formula (I) are, finally, obtained byhydrogenation of the compounds of general formula (7) in the presence ofhydrogen and of a palladium-based catalyst such aspalladium-on-charcoal, for example, in a solvent such as methanol, forexample.

The invention is therefore directed towards the use of at least onecompound of general formula (I) as defined above, as a medicament.

The invention is also directed towards the use, as a medicament, of atleast one compound of general formula (I) as defined above, in whichsaid compound has a tyrosinase-inhibiting activity.

The invention is also directed towards the use of at least one compoundof general formula (I) as defined above, for the preparation of apharmaceutical or cosmetic composition in which said compound has atyrosinase-inhibiting activity.

Advantageously, the compounds of the present invention have an IC₅₀value (dose which inhibits 50% of the enzymatic activity) with respectto tyrosinase of less than or equal to 10 μM, and more particularly lessthan or equal to 1 μM.

The invention also relates to a compound of general formula (I) for usethereof in the treatment and/or prevention of pigmentary disorders.

In fact, the compounds of general formula (I) according to the inventionare particularly suitable for use related to the treatment or preventionof pigmentary disorders such as melasma, chloasma, lentigines, senilelentigo, irregular hyperpigmentations related to photoageing, freckles,post-inflammatory hyperpigmentations due to an abrasion, a burn, a scar,dermatosis, a contact allergy; naevi, genetically determinedhyperpigmentations, hyperpigmentations of metabolic or drug-relatedorigin, melanomas or any other hyperpigmentary lesion.

A subject of the present invention is also a pharmaceutical compositionfor use in particular in the treatment of the abovementioned conditions,and which is characterized in that it comprises, in a pharmaceuticallyacceptable carrier that is compatible with the method of administrationselected for said composition, a compound of general formula (I) in oneof its isomer and enantiomer forms, or a salt thereof with apharmaceutically acceptable base.

The term “pharmaceutically acceptable carrier” is intended to mean amedium that is compatible with the skin, the mucous membranes and theskin appendages.

The composition according to the invention can be administeredtopically. Preferably, the pharmaceutical composition is packaged in aform suitable for topical application.

When used topically, the pharmaceutical composition according to theinvention is more particularly for use in the treatment of the skin andthe mucous membranes and may be in liquid, pasty or solid form, and moreparticularly in the form of ointments, creams, solutions or gels.

The compositions used for topical application have a concentration ofcompound according to the invention of generally between 0.001% and 10%by weight, preferably between 0.01% and 5% by weight, relative to thetotal weight of the composition.

The compounds of general formula (I) according to the invention alsofind a use in the cosmetics field, in particular in protecting againstthe harmful aspects of the sun, for preventing and/or combatingphotoinduced or chronological ageing of the skin and skin appendages.

A subject of the invention is therefore also a composition comprising,in a cosmetically acceptable carrier, at least one of the compounds ofgeneral formula (I). The term “cosmetically acceptable medium” isintended to mean a medium that is compatible with the skin, the mucousmembranes and the skin appendages.

A subject of the invention is also the cosmetic use of a compositioncomprising at least one compound of general formula (I), for preventingand/or treating the signs of ageing and/or the skin.

A subject of the invention is also the cosmetic use of a compositioncomprising at least one compound of general formula (I), for body orhair hygiene.

The cosmetic composition according to the invention containing, in acosmetically acceptable carrier, a compound of general formula (I), orone of its isomer and enantiomer forms or a salt thereof with acosmetically acceptable base, may be in particular in the form of acream, a milk, a gel, suspensions of microspheres or nanospheres orlipid or polymeric vesicles, impregnated pads, solutions, sprays, foams,sticks, soaps, washing bases or shampoos.

The concentration of compound of general formula (I) in the cosmeticcomposition is preferably between 0.001% and 10% by weight, relative tothe total weight of the composition.

The pharmaceutical and cosmetic compositions as described above may alsocontain inert additives, or even pharmacodynamically active additives asregards the pharmaceutical compositions, or combinations of theseadditives, and in particular:

wetting agents;

flavour enhancers;

preservatives, such as para-hydroxybenzoic acid esters;

stabilizers;

moisture regulators;

pH regulators;

osmotic pressure modifiers;

emulsifiers;

UV-A and UV-B screening agents;

antioxidants, such as α-tocopherol, butylated hydroxyanisole orbutylated hydroxytoluene, superoxide dismutase, ubiquinol; sodiummetabisulphite;

emollients;

moisturizing agents, such as glycerol. PEG 400, thiamorpholinone and itsderivatives, or urea;

antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine,S-benzylcysteamine, salts thereof or derivatives thereof, or benzoylperoxide.

Of course, those skilled in the art will take care to select theoptional compound(s) to be added to these compositions in such a waythat the advantageous properties intrinsically associated with thepresent invention are not, or not substantially, impaired by theenvisaged addition.

Several examples of the preparation of compounds of general formula (I)according to the invention, results for biological activity of thesecompounds and also various formulations based on such compounds will nowbe given by way of illustration and without any limiting nature.

EXAMPLE 1 3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid tort-butylester a) 2,4-Bis(benzyloxy)-1-bromobenzene

106.6 g (0.771 mol, 3 eq) of potassium carbonate (325 mesh) are added toa solution of 50.1 g (0.257 mol, 1 eq) of 4-bromoresorcinol at 97% in500 ml of acetone. The reaction medium is cooled to 5-10° C. and 75 ml(0.630 mol, 2.45 eq) of benzyl bromide are added dropwise. The reactionmedium is stirred at ambient temperature overnight and is then heated at50° C. for 2 hours. The solvent is evaporated off and the residue isthen taken up with a water/ethyl acetate mixture. The aqueous phase isextracted with ethyl acetate, and the organic phases are combined,washed with a saturated solution of sodium chloride, dried overmagnesium sulphate, filtered and evaporated. The residue (114.34 g) ischromatographed on silica gel (600 g), elution being carried out with90/10 heptane/dichloromethane.

94.4 g of 2,4-bis(benzyloxy)-1-bromobenzene are obtained in the form ofwhite crystals.

Yield=99%. b)3-(2,4-Bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acidtert-butyl ester

In a 100 ml three-necked flask, 5 g of 2,4-bis(benzyloxy)-1-bromobenzeneare dissolved in 60 ml of tetrahydrofuran. The mixture is cooled to −70°C. and then 11.4 ml of 2.5M n-butyllithium in hexane are added. Thereaction medium is stirred at −70° C. for 1 hour, and then 2.8 g of1-Boc-azetidine-3-one dissolved in 4 ml of THF are added dropwise. Thereaction medium is stirred at −70° C. for 2 hours and then left atambient temperature overnight. The reaction medium is poured into 40 mlof a 2M solution of hydrochloric acid and then extracted with 100 ml ofethyl acetate. The organic phases are combined, washed with 50 ml ofwater and then dried over magnesium sulphate and evaporated.

The residue is chromatographed on silica gel (AnaLogix SF40-80 gcolumn), elution being carried out with 80/20 heptanelethyl acetate. 2.2g of 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acidtert-butyl ester are obtained. Yield: 37%.

c) 3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester

1 g of 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acidtert-butyl ester are dissolved in a mixture of 20 ml of ethyl acetate/10ml of methanol, and then 0.2 g of palladium-on-charcoal at 10% is added.The reaction mixture is stirred for 24 hours under a hydrogenatmosphere. The reaction mixture is filtered and then the residue ischromatographed on silica gel (7/3 heptane/ethyl acetate). 0.16 g of3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester isobtained. Yield=28%.

¹H NMR (DMSO, 400 MHz): 1.38 (s, 9H): 3.72 (m, 1H); 3.85 (bm, 2H); 4.07(bm, 2H); 6.17 (dd, J=8.4 & 2.4 Hz, 1H); 6.27 (d, J=2.4 Hz, 1H); 6.92(d, J=8.4 Hz, 1H); 9.12 (s, 1H); 9.32 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 28.1, 55, 102.4, 105.9, 117.9, 127.6, 155.8,156.0, 157.0.

EXAMPLE 2 [3-(2,4-Dihydroxyphenyl)azetidin-1-yl]phenylmethanone a)3-(2,4-Bis(benzyloxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester

In a 25 ml round-bottomed flask, 1.35 g of potassium carbonate are addedin small portions to a solution of 0.86 g of3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester(Example 1) in 9 ml of methyl ethyl ketone.

0.93 ml of benzyl bromide are added dropwise and the reaction mixture isthen stirred for 2 hours at reflux. The reaction mixture is filtered andthe residue is then chromatographed on silica gel (70/30 heptane/ethylacetate).

1.1 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acidtert-butyl ester are obtained. Yield=76%.

b) 3-(2,4-Bis(benzyloxy)phenyl)azetidine trifluoroacetate

In a 25 ml round-bottomed flask, 1 g of3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid tert-butyl esteris dissolved in 10 ml of dichloromethane and then 2.5 ml oftrifluoroacetic acid are added. The reaction mixture is stirred for 2hours. The solvents are evaporated off and the residue is then taken upin isopropyl ether. 0.92 g of 3-(2,4-bis(benzyloxy)phenyl)azetidinetrifluoroacetate is obtained. Yield=90%.

c) [3-(2,4-Bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone

In a 10 ml round-bottomed flask, 0.25 g of3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate in 5 ml oftetrahydrofuran is dissolved in the presence of 0.1 ml ofN,N-diisopropylethylamine. 0.07 ml of benzoyl chloride is added and themixture is then stirred for 24 hours at ambient temperature. Thereaction mixture is extracted with ethyl acetate and the organic phasesare then combined and dried over magnesium sulphate. The residue ischromatographed on silica gel (9/1 heptane/ethyl acetate). 0.2 g of[3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is obtained.Yield=82%.

d) [3-(2,4-Dihydroxyphenyl)azetidin-1-yl]phenylmethanone

In a 10 ml round-bottomed flask, 0.2 g of[3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is dissolvedin 6 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at10%. The reaction mixture is stirred for 18 hours under a hydrogenatmosphere. The reaction mixture is filtered and the residue is thenchromatographed on silica gel (1/1 heptane/ethyl acetate).

0.08 g of [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone isobtained. Yield=67%.

¹H NMR (DMSO, 400 MHz): 3.86 (m, 1H): 4.04 (m, 1H); 4.29 (m, 2H); 4.58(t, J=8.6 Hz, 1H); 6.19 (dd, J=8.4 & 2.4 Hz, 1H); 6.28 (d. J=2.4 Hz,1H); 6.98 (d, J=8.4 Hz, 1H); 7.47 (m, 3H); 7.63 (d, J=8 Hz, 2H) 9.14 (s,1H); 9.37 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 29.3, 54.2, 58.7, 102.4, 105.9, 117.8, 127.7,127.8, 128.3, 130.7, 133.3, 156.0, 157.0, 168.9.

EXAMPLE 3 3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid pentylamidea) 3-(2,4-Bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide

In a 10 ml round-bottomed flask, 0.15 g of3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is dissolved in 3ml of tetrahydrofuran in the presence of 0.1 ml ofN,N-diisopropylethylamine. 0.04 ml of pentyl isocyanate is added and thereaction mixture is then stirred for 20 minutes at ambient temperature.The reaction mixture is extracted with ethyl acetate and the organicphases are then combined and dried over magnesium sulphate. The residueis chromatographed on silica gel (9/1 heptane/ethyl acetate). 0.1 g of3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide isobtained. Yield=67%.

b) 3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid pentylamide

In a 10 ml round-bottomed flask, 0.2 g of3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide isdissolved in 6 ml of methanol in the presence of 0.1 g ofpalladium-on-charcoal at 10%. The reaction mixture is stirred for 6hours under a hydrogen atmosphere. The reaction mixture is filtered andthe residue is then chromatographed on silica gel (95/5dichloromethane/methanol).

0.02 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid pentylamideis obtained. Yield=33%.

¹H NMR (DMSO, 400 MHz): 0.85 (t, J=7 Hz, 3H); 1.22 (m, 4H); 1.34 (m,2H); 2.94 (bm, 2H); 3.59 (bm, 1H); 3.73 (bm, 2H); 4.02 (bm, 2H); 6.17(m, 3H); 6.26 (d, J=2.4 Hz, 1H); 6.91 (d, J=8.4 Hz, 1H); 9.1 (bs, 1H);9.27 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 13.9, 21.9, 27.6, 28.5, 29.6, 55.0, 102.3,106.0, 118.5, 127.3, 155.8, 156.8, 159.9.

EXAMPLE 4 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acidtert-butyl ester a) 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 1 l three-necked flask, 10 g of N-Boc-3-hydroxypyrrolidine aredissolved in 350 ml of dimethyl sulphoxide in the presence of 52.3 ml oftriethylamine. 28 g of pyridine-sulphur trioxide complex dissolved in350 ml of dimethyl sulphoxide are added dropwise to the above solution.The reaction mixture is stirred for 4 hours at ambient temperature. Thereaction medium is acidified to pH 4.5-5 with a 1M solution ofhydrochloric acid and the reaction mixture is then extracted with ethylacetate. The organic phases are combined and then dried over anhydroussodium sulphate. The residue is filtered through silica gel (1/1heptane/ethyl acetate). 5.7 g of 3-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester are obtained. Yield: 58%.

b) 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

In a manner analogous to Examples 1b and 1c, but using3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester,3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester isobtained.

¹H NMR (DMSO, 400 MHz): 1.40 (s, 9H); 1.89 (m, 2H); 3.04 (t, J=9.5 Hz,1H); 3.23 (m, 1H); 3.36 (m, 2H): 3.57 (dd, J=7.6 & 10 Hz, 1H); 6.14 (dd,J=8.4 & 2.4 Hz, 1H); 6.28 (d, J=2.4 Hz, 1H): 6.82 (m, 1H); 9.06 (s, 1H):9.27 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 28.1, 29.9 & 30.8, 36.2 & 37.2, 45.2 & 45.4,50.7 & 51.1, 78.0, 102.5, 106.0, 127.1, 153.5, 155.5, 156.7.

EXAMPLE 5 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutylester a) 3-(2,4-Bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate

In a 50 ml round-bottomed flask, 1 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid tert-butylester (Example 4) are dissolved in 16 ml of dichloromethane and then 4ml of trifluoroacetic acid are added. The reaction mixture is stirredfor 1 hour. The solvents are evaporated off and the residue is thentaken up in isopropyl ether. 1.26 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate are obtained.Yield=76%.

b) 3-(2,4-Bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutylester

In a 10 ml round-bottomed flask, 0.25 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is dissolvedin 5 ml of tetrahydrofuran in the presence of 0.25 ml ofN,N-diisopropylethylamine. 0.108 g of isobutyl chloroformate is addedand the reaction mixture is stirred for 30 minutes at ambienttemperature. The reaction mixture is extracted with ethyl acetate andthe organic phases are then combined and dried over magnesium sulphate.The residue is chromatographed on silica gel (8/2 heptane/ethylacetate). 0.22 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylicacid isobutyl ester is obtained. Yield=66%.

c) 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutyl ester

In a 25 ml round-bottomed flask, 0.22 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl esteris dissolved in 6 ml of methanol in the presence of 0.1 g ofpalladium-on-charcoal at 10%. The reaction mixture is stirred for 18hours under a hydrogen atmosphere. The reaction mixture is filtered andthe residue is then chromatographed on silica gel (1/1 heptane/ethylacetate).

0.1 g of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutylester is obtained. Yield=75%.

¹H NMR (DMSO, 400 MHz): 0.88 (t, J=7 Hz, 6H); 1.80-2.07 (m, 3H); 3.10(q, J=9 Hz, 1H); 3.23-3.48 (m, 3H); 3.63 (m, 1H); 3.75 (m, 2H); 6.14(dd, J=8.4 & 2.4 Hz, 1H); 6.28 (d, J=2.4 Hz, 1H); 6.82 (m, 1H); 9.07 (s,1H); 9.29 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 18.9, 27.6, 30.0 & 30.8, 36.4 & 37.3, 45.0 &45.5, 50.6 & 51.0, 70.1, 102.5, 106.0, 117.5, 127.0, 154.1, 155.9,156.7.

EXAMPLE 6 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acidcyclohexylamide a) 3-(2,4-Bis(benzyloxy)phenyl)pyrrolidine-1-carboxylicacid cyclohexylamide

In a 10 ml round-bottomed flask, 0.25 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is dissolvedin 5 ml of tetrahydrofuran in the presence of 0.25 ml ofN,N-diisopropylethylamine. 0.1 g of cyclohexyl isocyanate is added andthe reaction mixture is stirred for 30 minutes at ambient temperature.The reaction mixture is extracted with ethyl acetate and the organicphases are then combined and dried over magnesium sulphate. The residueis chromatographed on silica gel (7/3 heptane/ethyl acetate). 0.23 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acidcyclohexylamide is obtained. Yield=66%.

b) 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid cyclohexylamide

In a 25 ml round-bottomed flask, 0.23 g of3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acidcyclohexylamide is dissolved in 4 ml of methanol in the presence of 3 mlof ethyl acetate and of 0.1 g of palladium-on-charcoal at 10%. Thereaction mixture is stirred for 18 hours under a hydrogen atmosphere.The reaction mixture is filtered and the residue is then chromatographedon silica gel (7/3 heptane/ethyl acetate).

0.095 g of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acidcyclohexylamide is obtained. Yield=100%.

¹H NMR (DMSO, 400 MHz): 1.17 (m, 4H); 1.55 (m, 1H); 1.60 (m, 4H); 1.86(m, 1H); 1.99 (m, 1H); 3.03 (t, J=9.2 Hz, 1H); 3.21 (q, J=9.2 Hz, 1H);3.38 (m, 3H); 3.56 (t, J=8 Hz, 1H); 5.67 (d, J=7.9 Hz, 1H); 6.14 (dd,J=8.4 & 2.4 Hz, 1H); 6.28 (d, J=2.4 Hz, 1H); 6.85 (d, J=8.2 Hz, 1H);9.04 (s, 1H); 9.25 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 25.1, 25.3, 30.6, 33.3, 36.9, 45.0, 48.7, 50.7,102.4, 105.9, 118.0, 127.0, 155.8, 155.9, 156.6.

EXAMPLE 7 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acidphenylamide

In a manner analogous to Example 6, but using phenyl isocyanate,3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid phenylamide isobtained.

¹H NMR (DMSO, 400 MHz): 1.94-2.09 (m, 2H); 3.23 (t, J=9.4 Hz, 1H); 3.37(m, 1H); 3.48 (m, 1H); 3.54 (m, 1H); 3.76 (dd, J=7.7 & 9.5 Hz, 1H); 6.17(dd, J=8.4 & 2.4 Hz, 1H); 6.30 (d, J=2.4 Hz, 1H); 6.89 (m, 2H); 7.21 (t,J=7.6 Hz, 2H); 7.51 (d, J=7.6 Hz, 2H), 9.08 (s, 1H); 9.31 (s, 1H).

¹³C NMR (DMSO, 100 MHz). 30.5, 37.0, 45.4, 51.0, 102.4, 106.0, 117.7,119.3, 121.4, 127.2, 128.2, 140.6, 153.8, 156.0, 156.7.

EXAMPLE 8 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid(4-fluorophenyl)amide

In a manner analogous to Example 6, but using 4-fluorophenyl isocyanate,3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid(4-fluorophenyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.93-2.08 (m, 2H); 3.24 (t, J=9.4 Hz, 1H); 3.37(m, 1H): 3.44 (m, 1H); 3.53 (m, 1H); 3.76 (dd, J=7.7 & 9.5 Hz, 1H); 6.17(dd, J=8.4 & 2.4 Hz, 1H): 6.30 (d, J=2.4 Hz, 1H); 6.91 (d, J=8.3 Hz,1H); 7.05 (t, J=8.8 Hz, 2H); 7.51 (m, 2H); 8.15 (s, 1H); 9.08 (s, 1H);9.31 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 30.5, 37.0, 45.4, 51.0, 102.5, 106.0, 114.7,117.7, 121.0, 127.1, 137.0, 155.9, 156.7, 158.3.

EXAMPLE 9 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid(4-trifluoromethylphenyl)amide

In a manner analogous to Example 6, but using 4-trifluoromethylphenylisocyanate, 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid(4-trifluoromethylphenyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.95-2.08 (m, 2H); 3.26 (t, J=9.4 Hz, 1H); 3.37(m, 1H); 3.44 (m, 1H); 3.57 (m, 1H); 3.77 (dd, J=7.7 & 9.5 Hz, 1H); 6.17(dd, J=8.4 & 2.4 Hz, 1H); 6.30 (d, J=2.4 Hz, 1H); 6.90 (d, J=8.3 Hz,1H); 7.56 (d. J=8.7 Hz, 1H); 7.76 (d, J=8.7 Hz, 2H); 8.52 (s, 1H); 9.08(s, 1H); 9.33 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 30.4, 37.0, 45.5, 51.0, 102.5, 106.0, 117.5,118.6, 121.1 (q), 124.6 (q), 125.4, 127.2, 153.38, 156.0, 156.7.

EXAMPLE 10 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid ethylester a) 4-(2,4-Bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylicacid ethyl ester

In a 500 ml three-necked flask. 20 g of2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 240 ml oftetrahydrofuran. The mixture is cooled to −70° C. and then 26 ml of 2.5Mn-butyllithium in hexane are added. The reaction medium is stirred at−70° C. for 1 hour, and then 11.1 g of 4-oxo-piperidine-1-carboxylicacid ethyl ester are added dropwise. The reaction medium is stirred at−70° C. for 2 hours and then left at ambient temperature overnight. Thereaction medium is poured into 100 ml of a 2M solution of hydrochloricacid and then extracted with 400 ml of ethyl acetate. The organic phasesare combined, washed with 150 ml of water and then dried over magnesiumsulphate and evaporated.

The residue is crystallized with a dichloromethane/heptane mixture. 16 gof 4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic acidethyl ester are obtained.

Yield: 62%. b) 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid ethylester

1 g of 4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylicacid ethyl ester is dissolved in a mixture of 50 ml of methanol, andthen 0.5 g of palladium-on-charcoal at 10% is added. The reactionmixture is stirred for 2 hours under a hydrogen atmosphere. The reactionmixture is filtered and the residue is then crystallized withdichloromethane. 0.5 g of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylicacid ethyl ester is obtained. Yield=86%.

¹H NMR (DMSO, 400 MHz): 1.17 (t, J=7 Hz, 3H); 1.38 (m, 2H); 1.64 (m,2H); 2.84 (m, 3H) 4.01 (m, 4H); 6.12 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d,J=2.4 Hz, 1H); 6.79 (d, J=8.3 Hz, 1H); 8.96 (s, 1H); 9.14 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 14.6, 31.6, 34.6, 44.2, 60.5, 102.3, 106.0,122.1, 126.7, 154.6, 155.2, 156.2.

EXAMPLE 11 [4-(2,4-Dihydroxyphenyl)piperidin-1-yl]phenylmethanone a)4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl ester

In a 100 ml round-bottomed flask. 9.7 g of potassium carbonate are addedin small portions to a solution of 6.2 g of4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester (Example10) in 62 ml of methyl ethyl ketone.

6.7 ml of benzyl bromide are added dropwise and the reaction mixture isthen stirred for 2 hours at reflux. The reaction mixture is filtered andthe residue is then chromatographed on silica gel (80/20 heptane/ethylacetate).9.8 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethylester are obtained. Yield=92%.

b) 4-(2,4-Bis(benzyloxy)phenyl)piperidine

In a 500 ml three-necked flask, 9 g of4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl ester aredissolved in 180 ml of ethanol, and then 40 ml of a 5M solution ofsodium hydroxide are added. The reaction mixture is brought to refluxfor 48 hours.

The reaction mixture is poured into 400 ml of water. The solid isfiltered off and then chromatographed on silica gel (98/2dichloromethane/methanol). 3.8 g of4-(2,4-bis(benzyloxy)phenyl)piperidine are obtained.

c) [4-(2,4-Bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone

In a 25 ml round-bottomed flask, 0.5 g of4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran isdissolved in the presence of 0.26 ml of N,N-diisopropylethylamine. 0.17ml of benzoyl chloride is added and the mixture is then stirred for 24hours at ambient temperature. The reaction mixture is extracted withethyl acetate and then the organic phases are combined and dried overmagnesium sulphate. The residue is chromatographed on silica gel (8/2heptane/ethyl acetate). 0.5 g of[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is obtained.Yield=80%.

d) [4-(2,4-Dihydroxyphenyl)piperidin-1-yl]phenylmethanone

In a 25 ml round-bottomed flask, 0.5 g of[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is dissolvedin 15 ml of methanol in the presence of 0.2 g of palladium-on-charcoalat 10%. The reaction mixture is stirred for 48 hours under a hydrogenatmosphere. The reaction mixture is filtered and the residue is thenchromatographed on silica gel (1/1 heptane/ethyl acetate).

0.3 g of [4-(2,4-dihydroxyphenyl)piperidin-1-yl]phenylmethanone isobtained. Yield=96%.

¹H NMR (DMSO, 400 MHz): 1.50 (bm, 2H); 1.59 (bm, 1H); 1.75, (bm, 1H);2.79 (bm, 1H); 2.97 (m, 1H); 3.11 (bm, 1H); 3.62 (bm, 1H); 4.59 (bm,1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.27 (d, J=2.4 Hz, 1H); 6.85 (d,J=8.3 Hz, 1H); 7.41 (m, 5H); 8.98 (s, 1H), 9.17 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.6, 47.9, 102.4, 106.0, 122.0, 126.6,126.9, 128.3, 129.2, 136.6, 139.6, 155.1, 156.1, 168.8, 170.3.

EXAMPLE 12 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidbutylamide a) 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acidbutylamide

In a 10 ml round-bottomed flask, 0.25 g of4-(2,4-bis(benzyloxy)phenyl)piperidine is dissolved in 5 ml oftetrahydrofuran in the presence of 0.23 ml of N,N-diisopropylethylamine.0.08 ml of butyl isocyanate is added and the reaction mixture is thenstirred for 20 minutes at ambient temperature. The reaction mixture isextracted with ethyl acetate, and then the organic phases are combinedand dried over magnesium sulphate. The residue is chromatographed onsilica gel (8/2 heptanelethyl acetate). 0.25 g of4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide isobtained. Yield=78%.

b) 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid butylamide

In a 25 ml round-bottomed flask, 0.25 g of4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide isdissolved in 9 ml of methanol in the presence of 0.1 g ofpalladium-on-charcoal at 10%. The reaction mixture is stirred for 4hours under a hydrogen atmosphere. The reaction mixture is filtered.

0.14 g of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid butylamideis obtained. Yield=90%.

¹H NMR (DMSO, 400 MHz): 0.86 (t, J=7 Hz, 3H); 1.30 (m, 2H); 1.37 (m,4H); 1.60 (m, 2H); 2.62 (m, 2H); 2.80 (m, 1H); 3.00 (m, 2H); 4.03 (m,2H); 6.12 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.38 (t,J=5.4 Hz, 1H): 6.77 (d, J=8.2 Hz, 1H); 8.95 (s, 1H): 9.11 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 13.8, 19.6, 31.7, 32.0, 34.7, 44.3, 102.3,106.0, 122.5, 126.7, 155.2, 156.0, 157.3.

EXAMPLE 13 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidpropylamide

In a manner analogous to Example 12a, but using propyl isocyanate,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid propylamide isobtained.

¹H NMR (DMSO, 400 MHz): 0.86 (t, J=7 Hz, 3H): 1.37 (m, 4H); 1.59 (m,2H); 2.65 (m, 2H); 2.79 (m, 1H); 2.97 (m, 2H): 4.03 (m, 2H); 6.12 (dd,J=8.4 & 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.41 (t, J=5.4 Hz, 1H);6.77 (d, J=8.2 Hz, 1H); 8.95 (s, 1H); 9.12 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 11.3, 23.0, 31.7, 34.7, 41.9, 44.3, 102.3,106.0, 122.5, 126.7, 155.2, 156.0, 157.3.

EXAMPLE 14 1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]butan-1-one

In a manner analogous to Example 11c, but using butanoyl chloride,1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]butan-1-one is obtained.

¹H NMR (DMSO, 400 MHz): 0.86 (t, J=7.5 Hz, 3H); 1.29-1.55 (m, 4H); 1.67(m, 2H); 2.27 (t. J=8 Hz, 2H); 2.48 (bm, 1H); 2.90 (t, J=11.6 Hz, 1H);3.02 (t, J=12.8 Hz, 1H); 3.91 (bd, J=12.8 Hz, 1H); 4.50 (bd, J=13.2 Hz,1H); 6.13 (dd. J=8.4 & 2.4 Hz, 1H); 6.24 (d, J=2.4 Hz, 1H); 6.77 (d,J=8.3 Hz, 1H); 8.93 (s, 1H), 9.11 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 14.3, 18.8, 32.1 & 32.9, 34.8, 35.1, 42.3 &46.3, 102.8, 106.5, 122.6, 127.2, 155.6, 156.6, 170.5.

EXAMPLE 151-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-methylpropan-1-one

In a manner analogous to Example 11c, but using 2-methylpropanoylchloride, 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-methylpropan-1-oneis obtained.

¹H NMR (DMSO, 400 MHz): 0.96 (2t, J=7.5 Hz, 6H); 1.28-1.46 (m, 2H); 1.68(m, 2H); 2.51 (bm, 1H); 2.87 (m, 2H); 3.05 (t, J=12.8 Hz, 1H); 4.01 (bd,J=12.8 Hz, 1H); 4.53 (bd, J=13.2 Hz, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H);6.25 (d, J=2.4 Hz, 1H); 6.79 (d, J=8.3 Hz, 1H); 8.97 (s, 1H), 9.15 (s,1H).

¹³C NMR (DMSO, 100 MHz): 19.3, 19.6, 28.9, 31.6 & 32.6, 34.7, 42.0 &45.6, 102.3, 106.0, 122.0, 126.7, 155.2, 156.1, 173.9.

EXAMPLE 16 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidphenylamide

In a manner analogous to Example 12a, but using phenyl isocyanate,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid phenylamide isobtained.

¹H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.70 (d, J=11.6 Hz, 2H); 2.82 (t,J=11.4 Hz, 2H); 2.90 (m, 1H); 4.23 (d, J=13.1 Hz, 2H); 6.14 (dd, J=8.4 &2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.82 (d, J=8.3 Hz, 1H); 6.91 (t,J=8.2 Hz, 1H); 7.21 (t, J=8 Hz, 2H); 7.45 (d, J=8 Hz, 2H); 8.47 (s, 1H);8.97 (s, 1H); 9.16 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.8, 34.7, 44.7, 102.4, 106.0, 119.5, 121.4,122.3, 126.8, 128.2, 140.7, 154.9, 155.2, 156.1.

EXAMPLE 17 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid(4-fluorophenyl)amide

In a manner analogous to Example 12a, but using 4-fluorophenylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid(4-fluorophenyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.69 (d, J=11.6 Hz, 2H); 2.82 (t,J=11.4 Hz, 2H); 2.90 (m, 1H); 4.22 (d, J=13.1 Hz, 2H); 6.14 (dd, J=8.4 &2.4 Hz, 1H); 6.28 (d, J=2.4 Hz, 1H); 6.81 (d, J=8.3 Hz, 1H); 7.08 (t,J=8.2 Hz, 2H); 7.46 (m, 2H); 8.51 (s, 1H); 9.00 (s, 1H); 9.16 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.8, 34.7, 44.6, 102.4, 106.0, 114.6, 121.2,122.3, 126.8, 137.0, 154.9, 155.2, 156.0, 156.1, 158.4.

EXAMPLE 18 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidp-tolylamide

In a manner analogous to Example 12a, but using p-tolyl isocyanate,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid p-tolylamide isobtained.

¹H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.69 (d, J=11.6 Hz, 2H); 2.22 (s,3H); 2.83 (t, J=11.4 Hz, 2H); 2.90 (m, 1H); 4.22 (d, J=13.1 Hz, 2H);6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.27 (d. J=2.4 Hz, 1H); 6.82 (d, J=8.3Hz, 1H); 7.02 (d, J=8.2 Hz, 2H); 7.34 (d, J=8 Hz, 2H); 8.37 (s, 1H);8.97 (s, 1H); 9.15 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 20.3, 31.8, 34.7, 44.6, 102.4, 106.0, 119.7,122.3, 126.8, 128.6, 130.2, 138.1, 154.9, 155.2, 156.1.

EXAMPLE 19 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidphenethylamide

In a manner analogous to Example 12a, but using phenethyl isocyanate,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid phenethylamide isobtained.

¹H NMR (DMSO, 400 MHz): 1.34 (m, 2H); 1.60 (d, J=11.6 Hz, 2H); 2.64-2.73(m, 4H); 2.83 (m, 1H); 3.22 (m, 2H); 4.02 (d, J=13.1 Hz, 2H); 6.14 (dd,J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.54 (m, 1H); 6.78 (d,J=8.3 Hz, 1H); 7.18 (m, 3H); 7.28 (m, 2H); 8.97 (s, 1H): 9.12 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 36.0, 41.9, 44.3, 102.4, 106.0,122.5, 125.8, 126.7, 128.2, 128.6, 139.9, 155.4.1, 156.0, 157.2.

EXAMPLE 20 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid(3-fluorophenyl)amide

In a manner analogous to Example 12a, but using 3-fluorophenylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid(3-fluorophenyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.69 (d, J=11.6 Hz, 2H); 2.82 (t,J=11.4 Hz, 2H); 2.90 (m, 1H); 4.22 (d, J=13.1 Hz, 2H); 6.14 (dd, J=8.4 &2.4 Hz, 1H); 6.27 (d, J=2.4 Hz, 1H); 6.70 (m, 1H); 6.81 (d, J=8.3 Hz,1H); 7.24 (m, 2H); 7.47 (d, J=18 Hz, 1H); 8.70 (s, 1H); 9.00 (s, 1H);9.17 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.8, 34.7, 44.7, 102.4, 106.0, 107.6, 114.9,122.2, 126.8, 129.6, 142.7, 154.5, 155.2, 156.1, 162.1.

EXAMPLE 21 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid((R)-1-phenylethyl)amide

In a manner analogous to Example 12a, but using((R)-1-isocyanatoethyl)benzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((R)-1-phenylethyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38 (m, 2H); 1.62 (m,2H); 2.82 (t. J=13 Hz, 2H); 2.83 (m, 1H); 4.22 (d, J=12.3 Hz, 2H); 4.84(m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.73 (d,J=7.9 Hz, 1H); 6.78 (d, J=8.3 Hz, 1H); 7.18 (m, 1H); 7.32 (m, 4H); 8.96(s, 1H); 9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 22.8, 31.7, 31.8, 44.4, 49.3, 102.4, 106.0,122.5, 125.9, 126.1, 126.7, 127.9, 146.3, 155.2, 156.0, 156.6.

EXAMPLE 22 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidmethylphenylamide

¹H NMR (DMSO, 400 MHz): 1.28 (m, 2H); 1.48 (d, J=12 Hz, 2H); 2.62 (t,J=12.6 Hz, 2H); 2.77 (m, 1H); 3.09 (s, 3H); 3.80 (d, J=13 Hz, 2H); 6.13(dd, J=8.4 & 2.4 Hz, 1H); 6.22 (d, J=2.4 Hz, 1H); 6.70 (d. J=7.9 Hz,1H); 7.11 (m, 3H); 7.35 (m, 2H); 8.96 (s, 1H); 9.09 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.2, 34.4, 38.8, 46.0, 102.3, 106.0, 122.2,122.6, 123.6, 126.6, 129.2, 146.7, 155.1, 156.0, 160.0.

EXAMPLE 23 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidpyridin-2-ylamide a) Pyridin-2-ylcarbamic acid 4-nitrophenyl ester

0.5 g of 2-aminopyridine is dissolved in 10 ml of dichloromethane andthen 1.18 g of 4-nitrophenyl chloroformate are added, as are 1.85 ml ofN,N-diisopropylethylamine. The reaction mixture is stirred for one hourat ambient temperature. 50 ml of water are added to the reaction mixtureand then the medium is extracted with 50 ml of dichloromethane. Thesolvents are evaporated off and then the solid is used in the next stagewithout further purification.

b) 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acidpyridin-2-ylamide

0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinium chloride is suspendedin 5 ml of dimethylformamide and then 0.43 ml ofN,N-diisopropylethylamine is added, as is 0.38 g of pyridin-2-ylcarbamicacid 4-nitrophenyl ester in solution in 2 ml of dimethylformamide. Thereaction mixture is stirred for 24 hours at 80′C.

It is heated at 80° C. for 24 hours. 50 ml of water are added, and thereaction mixture is then extracted with 50 ml of ethyl acetate. Thesolvents are evaporated off and then the residue is chromatographed onsilica gel (70/30 heptane/ethyl acetate). 20 mg of4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acidpyridin-2-ylamide are obtained.

c) 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid pyridin-2-ylamide

20 mg of 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acidpyridin-2-ylamide are dissolved in 20 ml of ethyl acetate and then 1 mlof methanol is added. 10 mg of palladium-on-charcoal at 10% are added,and then the reaction mixture is stirred for 18 hours under a hydrogenatmosphere. The mixture is filtered and the residue is then crystallizedfrom an ethyl acetate/heptane mixture. 5 mg of4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid pyridin-2-ylamide.Yield: 39%

¹H NMR (DMSO, 400 MHz): 1.458 (m, 2H); 1.68 (m, 2H); 2.85 (m, 3H); 4.26(d, J=13.6 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz,1H); 6.81 (d, J=7.9 Hz, 1H): 6.95 (m, 1H); 7.66 (m, 1H); 7.78 (d, J=7.9Hz, 1H); 8.21 (m, 1H); 8.97 (s, 1H); 9.09 (s, 1H), 9.15 (s, 1H).

EXAMPLE 24 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylethyl)amide

In a manner analogous to Example 12a, but using((S)-1-isocyanatoethyl)benzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylethyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38 (m, 2H); 1.62 (m,2H); 2.82 (t, J=13 Hz, 2H); 2.83 (m, 1H); 4.22 (d, J=12.3 Hz, 2H); 4.84(m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.73 (d,J=7.9 Hz, 1H); 6.78 (d, J=8.3 Hz, 1H); 7.18 (m, 1H); 7.32 (m, 4H); 8.96(s, 1H); 9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 22.8, 31.7, 31.8, 44.4, 49.3, 102.4, 106.0,122.5, 125.9, 126.1, 126.7, 127.9, 146.3, 155.2, 156.0, 156.6.

EXAMPLE 25 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylpropyl)amide

In a manner analogous to Example 12a, but using((S)-1-isocyanatopropyl)benzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylpropyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 0.82 (t, J=7.1 Hz, 3H): 1.37 (m, 2H); 1.67 (m,4H); 2.67 (m, 2H); 2.83 (m, 1H); 4.12 (d, J=12.3 Hz, 2H); 4.56 (m, 1H);6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.65 (d, J=7.9Hz, 1H); 6.77 (d, J=8.3 Hz, 1H); 7.18 (m, 1H); 7.29 (m, 4H); 8.96 (s,1H); 9.11 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 11.4, 29.3, 31.7, 34.7, 44.5, 55.8, 102.4,106.0, 122.5, 126.1, 126.4, 126.7, 127.9, 145.4, 155.1, 156.0, 156.9.

EXAMPLE 26(R)-2-Amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-onea)(R)-1-Benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl)carbamicacid benzyl ester

In a 50 ml round-bottomed flask, 0.615 g of Z-L-phenylalanine isdissolved in 10 ml of dimethylformamide, and 0.43 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and also 0.305 g of1-hydroxybenzotriazole (HOBT) are added, and the reaction mixture isthen stirred for 5 minutes at ambient temperature.

1 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinium hydrochloride and also0.36 ml of diisopropylamine are added. The reaction mixture is stirredfor 1 hour at ambient temperature. The reaction medium is washed with 20ml of 5% citric acid and then extracted with 20 ml of ethyl acetate, theorganic phase is washed with 20 ml of a 1M solution of sodium hydroxide,and the organic phase is dried over magnesium sulphate. Afterevaporation of the solvents, the crude product is chromatographed onsilica gel. 1.23 g of{(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl}carbamicacid benzyl ester are obtained.

b)(R)-2-Amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one

In a 25 ml round-bottomed flask, 1.23 g of{(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl}carbamicacid benzyl ester are dissolved in 15 ml of methanol and also 15 ml ofethyl acetate in the presence of 0.25 g of palladium-on-charcoal at 10%.The reaction mixture is stirred for 18 hours under a hydrogenatmosphere. The reaction mixture is filtered. The residue ischromatographed on silica gel (95/5 dichloromethane/methanol). 0.625 gof(R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-oneis obtained. Yield=64%.

¹H NMR (DMSO, 400 MHz): 0.6 (m, 1H); 1.09 (m, 1H); 1.30-1.75 (m, 5H);2.56-2.97 (m, 4H); 3.94 (m, 2H); 4.51 (d, J=12.8 Hz, 1H); 6.11 (m, 1H);6.24 (m, 1H); 6.57 & 6.77 (d, J=8.3 Hz, 1H); 7.18-7.40 (m, 5H); 8.97 (s,1H); 9.11 & 9.15 (s, 1H).

¹³C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6, 32.3, 31.1, 34.6,42.0, 42.2, 42.7, 45.3, 45.6, 51.3, 51.6, 102.3, 105.9, 121.9, 126.0,126.7, 127.9, 128.1, 129.4, 138.5, 155.0, 156.0, 172.6.

EXAMPLE 271-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one

In a manner analogous to Example 11c, but using 3-phenylpropionylchloride, 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-oneis obtained.

¹H NMR (DMSO, 400 MHz): 1.33 (m, 2H): 1.63 (m, 2H); 2.50-2.70 (m, 3H);2.80-3.0 (m, 4H); 3.92 (d, J=12.8 Hz, 1H); 4.53 (d, J=12.8 Hz, 1H); 6.14(dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.75 (d, J=7.9 Hz,1H); 7.15-7.29 (m, 5H); 8.97 (s, 1H); 9.11 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 30.9, 31.6, 32.2, 33.9, 34.5, 42.0, 45.8,102.4, 106.0, 122.1, 125.8, 126.7, 128.2, 128.4, 141.5, 155.2, 156.1,169.5.

EXAMPLE 28 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid2-fluorobenzylamide

In a manner analogous to Example 12a, but using 2-fluorobenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid2-fluorobenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.40 (m, 2H); 1.63 (m, 2H); 2.76 (t, J=13 Hz,2H); 2.84 (m, 1H); 4.02 (d, J=12.3 Hz, 2H): 4.28 (d, J=5.5 Hz, 2H); 6.14(dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.73 (d, J=7.9 Hz,1H); 7.03 (t. J=5.6 Hz, 1H); 7.16 (m, 2H); 7.28 (m, 2H); 8.96 (s, 1H);9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 37.0, 44.4, 102.4, 106.0, 114.7,122.4, 124.1, 126.7, 127.7, 128.2, 129.0, 155.2, 156.0, 157.2, 158.6,161.0

EXAMPLE 29 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid3-fluorobenzylamide

In a manner analogous to Example 12a, but using 3-fluorobenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid3-fluorobenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.38 (m, 2H); 1.63 (m, 2H); 2.73 (t, J=13 Hz,2H); 2.86 (m, 1H); 4.04 (d, J=12.3 Hz, 2H); 4.23 (d, J=5.5 Hz, 2H); 6.14(dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.79 (d, J=7.9 Hz,1H); 7.06 (m, 4H); 7.34 (m, 1H); 8.96 (s, 1H); 9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.8, 24.7, 43.1, 44.5, 102.5, 106.1, 113.0 &113.2, 113.5 & 113.7, 122.5, 123.0, 126.8, 130.0, 144.6, 155.3, 156.1,157.3.

EXAMPLE 30 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid4-fluorobenzylamide

In a manner analogous to Example 12a, but using 4-fluorobenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid4-fluorobenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.38 (m, 2H); 1.63 (m, 2H); 2.71 (t, J=13 Hz,2H); 2.84 (m, 1H); 4.04 (d, J=12.3 Hz, 2H); 4.21 (d, J=5.5 Hz, 2H); 6.14(dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.78 (d, J=7.9 Hz,1H); 7.05 (t, J=5.6 Hz, 1H); 7.13 (m, 2H); 7.28 (m, 2H); 8.96 (s, 1H);9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 42.8, 44.4, 102.4, 106.0, 114.7,122.4, 126.7, 128.8, 137.4, 155.2, 156.0, 157.2, 159.7 & 162.1.

EXAMPLE 31 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acidbenzylamide

In a manner analogous to Example 12a, but using benzyl isocyanate,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid benzylamide isobtained.

¹H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.63 (m, 2H); 2.72 (t. J=13 Hz,2H); 2.85 (m, 1H); 4.02 (d, J=12.3 Hz, 2H); 4.24 (d, J=5.5 Hz, 2H); 6.14(dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.79 (d, J=7.9 Hz,1H); 7.05 (t, J=5.6 Hz, 1H); 7.24 (m, 5H); 7.28 (m, 2H); 8.96 (s, 1H);9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 43.5, 44.4, 102.4, 106.0, 122.4,126.3, 126.7, 126.9, 128.0, 141.2, 155.2, 156.0, 157.3.

EXAMPLE 32 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid2-methylbenzylamide

In a manner analogous to Example 12a, but using 2-methylbenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid2-methylbenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.40 (m, 2H); 1.62 (m, 2H); 2.27 (s, 3H); 2.73(t, J=13 Hz, 2H); 2.85 (m, 1H); 4.10 (d, J=12.3 Hz, 2H); 4.22 (d, J=5.5Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.79 (d,J=7.9 Hz, 1H); 6.90 (t. J=5.6 Hz, 1H); 7.09-7.20 (m, 4H); 7.28 (m, 2H);9 (bs, 1H); 9.12 (bs, 1H).

¹³C NMR (DMSO, 100 MHz): 18.6, 31.8, 34.7, 41.4, 44.5, 102.4, 106.0,122.4, 125.5, 126.2, 126.7, 126.9, 129.6, 135.0, 138.7, 155.2, 156.0,157.3.

EXAMPLE 33 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid3-methylbenzylamide

In a manner analogous to Example 12a, but using 3-methylbenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid3-methylbenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.40 (m, 2H); 1.62 (m, 2H); 2.28 (s, 3H); 2.72(t, J=13 Hz, 2H); 2.86 (m, 1H); 4.02 (d, J=12.3 Hz, 2H): 4.20 (d, J=5.5Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.78 (d,J=7.9 Hz, 1H); 7.00-7.06 (m, 4H); 7.18 (t, J=7.6 Hz, 1H); 8.99 (s, 1H);9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 21.0, 31.7, 34.7, 43.4, 44.5, 102.4, 106.0,122.5, 124.1, 126.7, 126.9, 127.6, 127.9, 136.9, 141.1, 155.2, 156.0,157.3.

EXAMPLE 34 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid4-methylbenzylamide

In a manner analogous to Example 12a, but using 4-methylbenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid4-methylbenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.62 (m, 2H); 2.27 (s, 3H); 2.71(t, J=13 Hz, 2H); 2.84 (m, 1H); 4.08 (d, J=12 Hz, 2H); 4.19 (d, J=5.5Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.78 (d,J=7.9 Hz, 1H); 6.99 (t, J=5.6 Hz, 1H); 7.12 (2d, J=8 Hz, 4H); 8.96 (s,1H); 9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 20.8, 31.9, 34.9, 43.4, 44.6, 102.6, 106.2,122.7, 126.9, 127.2, 128.7, 135.4, 138.4, 155.4, 156.3, 157.5.

EXAMPLE 35 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid2-methoxybenzylamide

In a manner analogous to Example 12a, but using 2-methoxybenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid2-methoxybenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.63 (m, 2H); 2.74 (t, J=13 Hz,2H); 2.86 (m, 1H); 3.79 (s, 3H); 4.11 (d, J=12.3 Hz, 2H); 4.22 (d, J=5.5Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H);6.79-6.95 (m, 4H); 7.13-7.22 (m, 2H); 9.00 (bs, 1H); 9.14 (bs, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 38.3, 44.5, 55.2, 102.4, 106.0,110.1, 119.9, 122.5, 126.7, 126.9, 127.3, 128.6, 155.2, 156.1, 156.3,157.4.

EXAMPLE 36 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid3-methoxybenzylamide

In a manner analogous to Example 12a, but using 3-methoxybenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid3-methoxybenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.63 (m, 2H); 2.72 (t, J=13 Hz,2H); 2.86 (m, 1H); 3.73 (s, 3H); 4.09 (d, J=12.3 Hz, 2H); 4.21 (d, J=5.5Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.79 (m,4H); 7.03 (t, J=5.6 Hz, 1H); 7.22 (t, J=8 Hz, 1H); 9.02 (bs, 1H): 9.10(bs, 1H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 43.4, 44.5, 54.9, 102.4, 106.0,111.6, 112.6, 119.1, 122.5, 126.7, 129.0, 142.9, 155.2, 156.0, 157.3,159.2.

EXAMPLE 37 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid4-methoxybenzylamide

In a manner analogous to Example 12a, but using 4-methoxybenzylisocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid4-methoxybenzylamide is obtained.

¹H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.62 (m, 2H): 2.70 (t, J=13 Hz,2H): 2.84 (m, 1H); 3.72 (s, 3H); 4.08 (d, J=12 Hz, 2H); 4.16 (d, J=5.5Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.78 (d,J=7.9 Hz, 1H); 6.87 (d, J=8 Hz, 2H); 7.12 (t, J=5.6 Hz, 1H); 7.18 (d,J=8 Hz, 2H); 9.06 (s, 2H).

¹³C NMR (DMSO, 100 MHz): 31.7, 34.7, 42.9, 44.4, 55.0, 102.4, 106.0,113.4, 122.4, 126.7, 128.3, 133.2, 155.2, 156.1, 157.3, 157.9.

EXAMPLE 38 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-p-tolylethyl)amide

In a manner analogous to Example 12a, but using((S)-1-isocyanatoethyl)-4-methylbenzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-p-tolylethyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38 (m, 2H); 1.62 (m,2H); 2.26 (s, 3H); 2.67 (t, J=13 Hz, 2H); 2.83 (m, 1H); 4.11 (d, J=12.3Hz, 2H); 4.84 (m, 1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz,1H); 6.67 (d, J=7.9 Hz, 1H); 6.77 (d, J=8.3 Hz, 1H); 7.09 (d, J=8 Hz,2H); 7.20 (d, J=8 Hz, 2H); 8.96 (s, 1H); 9.12 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 18.5, 20.6, 22.9, 31.8, 34.7, 44.4, 49.0,102.4, 106.0, 122.5, 125.8, 126.7, 128.5, 135.0, 143.2, 155.2, 156.0,156.6.

EXAMPLE 39 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid[(S)-1-(4-fluorophenyl)ethyl]amide

In a manner analogous to Example 12a, but using1-fluoro-4-((S)-1-isocyanatoethyl)benzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid[(S)-1-(4-fluorophenyl)ethyl]amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38 (m, 2H); 1.62 (m,2H); 2.67 (t, J=13 Hz, 2H); 2.83 (m, 1H); 4.09 (d, J=12.3 Hz, 2H); 4.84(m, 1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.74 (d,J=7.9 Hz, 1H); 6.78 (d, J=8.3 Hz, 1H); 7.09 (t, J=8.9 Hz, 2H); 7.35 (m,2H); 8.96 (s, 1H); 9.12 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 22.8, 31.7, 34.7, 44.4, 48.7, 102.4, 106.0,114.5, 122.4, 126.7, 127.8, 142.4, 155.2, 156.0, 156.5, 160.7 (d, J=241Hz).

EXAMPLE 40 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid(S)-indan-1-ylamide

In a manner analogous to Example 12a, but using (S)-1-isocyanatoindane,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid (S)-indan-1-ylamideis obtained.

¹H NMR (DMSO, 400 MHz): 1.38 (m, 2H); 1.62 (m, 2H); 1.86 (m, 1H); 2.36(m, 1H); 2.68-2.93 (m, 5H); 4.13 (d, J=12.3 Hz, 2H); 5.23 (m, 1H); 6.14(dd. J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.71 (d, J=7.9 Hz,1H); 6.80 (d, J=8.3 Hz, 1H); 7.20 (m, 4H); 9.07 (bs, 2H).

¹³C NMR (DMSO, 100 MHz): 29.6, 31.7, 33.2, 34.7, 44.5, 55.3, 102.4,106.0, 122.5, 123.9, 124.3, 126.1, 126.7, 126.9, 142.6, 145.4, 155.2,156.0, 157.4.

EXAMPLE 41 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-naphthalen-1-ylethyl)amide

In a manner analogous to Example 12a, but using1-((S)-1-isocyanatoethyl)naphthalene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-naphthalen-1-ylethyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.37 (m, 2H); 1.49 (d, J=7.1 Hz, 3H); 1.62 (m,2H); 2.70 (t, J=13 Hz, 2H); 2.84 (m, 1H); 4.14 (t, J=12 Hz, 2H); 5.66(m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.75 (d,J=7.9 Hz, 1H); 6.91 (d, J=7.7 Hz, 1H); 7.53 (m, 4H); 7.79 (d, J=8 Hz,1H); 7.93 (d, J=8 Hz, 1H); 8.16 (d, J=8 Hz, 1H); 8.97 (s, 1H); 9.13 (s,1H).

¹³C NMR (DMSO, 100 MHz): 22.0, 31.7, 34.6, 44.6, 45.5, 102.4, 106.0,122.2, 122.5, 123.3, 125.3, 125.4, 125.9, 126.7, 126.7, 128.5, 130.4,133.3, 141.8, 155.2, 156.0, 156.5.

EXAMPLE 42 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-naphthalen-2-ylethyl)amide

In a manner analogous to Example 23a, but using(S)-1-naphthalen-2-ylethylamine, and then repeating the sequence 23b and23c, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-naphthalen-2-ylethyl)amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.35 (m, 2H); 1.46 (d, J=7.1 Hz, 3H): 1.62 (m,2H); 2.70 (t, J=13 Hz, 2H); 2.85 (m, 1H); 4.14 (d. J=12.9 Hz, 2H); 5.01(m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H): 6.77 (d,J=7.9 Hz, 1H); 6.85 (d. J=7.7 Hz, 1H); 7.43-7.50 (m, 3H); 7.77 (s, 1H);7.85 (m, 3H); 8.97 (s, 1H); 9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 22.6, 31.2, 34.6, 44.5, 49.5, 102.4, 106.0,122.5, 123.8, 125.1, 125.3, 125.9, 126.7, 127.4, 127.5, 131.9, 132.8,143.8, 155.2, 156.0, 156.7.

EXAMPLE 43 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid[(S)-1-(4-methoxyphenyl)ethyl]amide

In a manner analogous to Example 12a, but using1-((S)-1-isocyanatoethyl)-4-methoxybenzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid[(S)-1-(4-methoxyphenyl)ethyl]amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.33 (d, J=7.1 Hz, 3H); 1.38 (m, 2H); 1.62 (m,2H); 2.66 (t, J=13 Hz, 2H); 2.83 (m, 1H); 3.72 (s, 3H); 4.06 (d, J=12.3Hz, 2H); 4.79 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz,1H); 6.64 (d, J=7.9 Hz, 1H); 6.78 (d, J=8.3 Hz, 1H); 6.85 (d, J=8.6 Hz,2H); 7.23 (d, J=8.6 Hz, 2H): 8.96 (s, 1H): 9.13 (s, 1H).

¹³C NMR (DMSO, 100 MHz): 22.9, 31.7, 34.7, 44.4, 48.6, 55.0, 102.4,106.0, 113.3, 122.5, 126.7, 127.0, 138.2, 155.2, 156.0, 156.6, 157.7.

EXAMPLE 44 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid[(S)-1-(3-methoxyphenyl)ethyl]amide

In a manner analogous to Example 12a, but using1-((S)-1-isocyanatoethyl)-3-methoxybenzene,4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid[(S)-1-(3-methoxyphenyl)ethyl]amide is obtained.

¹H NMR (DMSO, 400 MHz): 1.33 (d, J=7.1 Hz, 3H); 1.38 (m, 2H); 1.62 (m,2H); 2.68 (t, J=13 Hz, 2H); 2.84 (m, 1H); 3.73 (s, 3H); 4.10 (d, J=12.3Hz, 2H); 4.81 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H): 6.26 (d, J=2.4 Hz,1H); 6.70-6.79 (m, 5H); 7.20 (t, J=8.1 Hz, 1H); 8.96 (s, 1H); 9.13 (s,1H).

¹³C NMR (DMSO, 100 MHz): 22.9, 31.8, 34.6, 44.4, 49.3, 54.9, 102.4,106.0, 111.3, 111.8, 118.2, 122.5, 126.7, 129.0, 148.0, 155.2, 156.0,156.7, 159.1.

EXAMPLE 45(S)-2-Amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one

In a manner analogous to Example 26, but using Z-D-phenylalanine,(S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-oneis obtained.

¹H NMR (DMSO, 400 MHz): 0.6 (m, 1H); 1.09 (m, 1H); 1.30-1.75 (m, 5H);2.56-2.97 (m, 4H); 3.94 (m, 2H); 4.51 (d, J=12.8 Hz, 1H); 6.11 (m, 1H);6.24 (m, 1H); 6.57 & 6.77 (d, J=8.3 Hz, 1H); 7.18-7.40 (m, 5H); 8.97 (s,1H); 9.11 & 9.15 (s, 1H).

¹³C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6, 32.3, 31.1, 34.6,42.0, 42.2, 42.7, 45.3, 45.6, 51.3, 51.6, 102.3, 105.9, 121.9, 126.0,126.7, 127.9, 128.1, 129.4, 138.5, 155.0, 156.0, 172.6.

EXAMPLE 46 4-(5-Fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylethyl)amide a) 1,5-Bis(benzyloxy)-2-fluoro-4-nitrobenzene

2.82 g (70.6 mmol, 2.5 eq) of sodium hydride at 60% are added to asolution of 7.6 g (70.6 mmol, 2.5 eq) of benzyl alcohol in 100 ml oftetrahydrofuran. The reaction medium is stirred at ambient temperaturefor 1½ hours and then 5.0 g (28.2 mmol, 1 eq) of1,2,4-trifluoro-5-nitrobenzene in solution in 50 ml of tetrahydrofuranare added dropwise. The reaction medium is refluxed for 3 hours. Thereaction medium is treated with 150 ml of 1M hydrochloric acid andextracted with ethyl acetate. The organic phases are combined, washedwith a saturated solution of sodium chloride, dried over magnesiumsulphate, filtered and evaporated. The residue is chromatographed onsilica gel, elution being carried out with 90/10 heptane/ethyl acetate.

1.68 g of 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene are obtained.

Yield=17%. b) 1,5-Bis(benzyloxy)-2-fluoro-4-aminobenzene

508 mg (9.5 mmol, 2 eq) of ammonium chloride, followed by 2.23 g (34.2mmol, 7.2 eq) of zinc powder, are added to a solution of 1.68 g (4.75mmol, 1 eq) of 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene in 50 ml ofwater. The reaction medium is refluxed for 4 hours. The cooled reactionmedium is extracted with ethyl acetate. The organic phases are combined,washed with a saturated solution of sodium chloride, dried overmagnesium sulphate, filtered and evaporated. The residue ischromatographed on silica gel, elution being carried out with 85/15heptane/ethyl acetate.

930 mg of 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzene are obtained.

Yield=61%. c) 1,5-Bis(benzyloxy)-2-fluoro-4-iodobenzene

7 ml of 6M hydrochloric acid are added to a solution of 3.20 g (9.9mmol, 1 eq) of 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzene in 40 ml ofN,N-dimethylformamide, cooled to 0° C. 683 mg (9.9 mmol, 1 eq) of sodiumnitrite in solution in 7 ml of water are added and the reaction mediumis stirred at 0° C. for 1 hour. 1.64 g (9.9 mmol, 1 eq) of potassiumiodide in solution in 8 ml of water are added, followed by 190 mg (1.0mmol, 0.1 eq) of copper iodide, and then the reaction medium is stirredat ambient temperature overnight. The reaction medium is treated with asaturated solution of ammonium chloride and extracted with ethylacetate. The organic phases are combined, washed with a saturatedsolution of sodium chloride, dried over magnesium sulphate, filtered andevaporated. The residue is chromatographed on silica gel, elution beingcarried out with 75/25 heptane/dichloromethane. 3.59 g of1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene are obtained.

Yield=68%. d)4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidtert-butyl ester

4.0 ml (9.9 mmol, 1.2 eq) of 2.5M n-butyllithium in hexane are added toa solution of 3.59 g (8.26 mmol, 1 eq) of1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene in 40 ml of tetrahydrofuran,cooled to −70′C. The reaction medium is stirred at −70° C. for 25minutes and 1.97 g (9.9 mmol, 1.2 eq) of 1-boc-4-piperidone in solutionin 20 ml of tetrahydrofuran are added. The reaction medium is stirred at−70° C. for 1 hour and is then left to return to ambient temperatureovernight. 30 ml of a saturated solution of ammonium chloride, to which4 ml of 2M hydrochloric acid have been added, are added to the reactionmedium, which is stirred for 20 minutes and is then extracted with ethylacetate. The organic phases are combined, dried over magnesium sulphateand evaporated. The residue is chromatographed on silica gel, elutionbeing carried out with 95/5 heptane/ethyl acetate then 75/25heptane/ethyl acetate (with 0.1% of TEA).

860 mg of a mixture of4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidtert-butyl ester (25%) and of 1-boc-4-piperidone are obtained in theform of a yellow oil which crystallizes. Yield=5%.

e) 4-(5-Fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A mixture of 860 mg (0.42 mmol, 1 eq) of4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidtert-butyl ester at 35% in 10 ml of ethyl acetate, in the presence of200 mg of palladium-on-charcoal at 10%, is stirred at ambienttemperature under a hydrogen pressure of 5 bar for 17 hours. 5 ml ofmethanol are added and the reaction medium is stirred at ambienttemperature under a hydrogen pressure of 5 bar for 29 hours. Thereaction medium is filtered through filter paper and the filtrate isevaporated off. The residue is chromatographed on silica gel, elutionbeing carried out with 60/40 heptane/ethyl acetate. 192 mg of4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester are obtained. Yield=100%.

f) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidtert-butyl ester

241 mg (1.74 mmol, 3 eq) of potassium carbonate (325 mesh) are added toa solution of 181 mg (0.58 mmol, 1 eq) of4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid tert-butylester in 3 ml of acetone. 152 μl (1.28 mmol, 2.2 eq) of benzyl bromideare added dropwise. The reaction medium is heated at 50° C. for 20hours. The solvent is evaporated off and then the residue is taken upwith a water/ethyl acetate mixture. The aqueous phase is extracted withethyl acetate, and the organic phases are combined, washed with asolution of sodium hydrogen carbonate and then with a saturated solutionof sodium chloride, dried over magnesium sulphate, filtered andevaporated. The residue is chromatographed on silica gel, elution beingcarried out with 85/15 heptane/ethyl acetate.

188 mg of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylicacid tert-butyl ester are obtained. Yield=66%.

g) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine

280 μl (3.7 mmol, 10 eq) of trifluoroacetic acid are added to a solutionof 184 mg (0.37 mmol, 1 eq) of4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidtert-butyl ester in 3 ml of dichloromethane. The reaction medium isstirred at ambient temperature for 1 hour. The reaction medium istreated with 10 ml of water and then extracted with dichloromethane. Theorganic phases are combined, washed with a saturated solution of sodiumhydrogen carbonate and then with a saturated solution of sodiumchloride, dried over magnesium sulphate and evaporated. 150 mg of4-(2,4-bis(benzyloxy)-5-fluorophenyl)pipendine are obtained. Yield=100%.

h) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid((S)-1-phenylethyl)amide

65 μl (0.45 mmol, 1.2 eq) of (S)-(−)-phenylethyl isocyanate are added toa solution of 147 mg (0.37 mmol, 1 eq) of4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine in 3 ml oftetrahydrofuran in the presence of 64 μl (0.37 mmol, 1 eq) ofdimethylethylamine. The reaction medium is stirred at ambienttemperature for 50 minutes. The reaction is stopped by adding 5 ml ofwater, and then extracted with ethyl acetate. The organic phases arecombined and dried over magnesium sulphate. The solvent is evaporatedoff and the residue is chromatographed on silica gel, elution beingcarried out with 60/40 heptane/ethyl acetate. 178 mg of4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidphenylamide are obtained. Yield=89%.

i) 4-(5-Fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylethyl)amide

A mixture of 174 mg (0.32 mmol, 1 eq) of4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acidphenylamide in 1 ml of ethyl acetate and of 2 ml of methanol in thepresence of 51 mg (30% by mass) of palladium-on-charcoal at 10% isstirred at ambient temperature under atmospheric hydrogen pressure for 8hours. The reaction medium is filtered through filter paper and thefiltrate is evaporated off. The residue is chromatographed on silicagel, elution being carried out with 30/70 heptane/ethyl acetate. 83 mgof 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid((S)-1-phenylethyl)amide are obtained.

Yield=72%.

¹H NMR (DMSO, 400 MHz): 1.35-1.45 (m, 5H); 1.53 (m, 2H); 2.67 (t, J=13Hz, 2H); 2.83 (m, 1H); 4.11 (d, J=12.3 Hz, 2H): 4.83 (m, 1H); 6.43 (d,J=8.0 Hz, 1H); 6.73 (m, 2H); 7.14-7.40 (m, 5H); 9.11 (s, 1H); 9.40 (s,1H).

¹³C NMR (DMSO, 100 MHz): 23.0, 31.6, 34.6, 44.2, 49.3, 104.5, 113.3 (d,J=19 Hz), 122.4, (d, J=5 Hz), 125.9, 126.1, 127.9, 142.4, 144.6 (d,J=228 Hz), 146.3, 150.4, 155.5.

EXAMPLE 47(R)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone

In a manner analogous to Example 26, but using (R)-hydroxyphenylaceticacid,(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanoneis obtained.

¹H NMR (DMSO, 400 MHz): (hindrance of rotation) 0.6 (m, 0.5H); 1.30-1.70(m, 3.5H): 2.5-3 (m, 2H); 4.0 (m, 1H); 4.51 (m, 1H); 5.37-5.57 (m, 2H);6.07 (m, 1H); 6.24 (m, 1H); 6.48 & 6.72 (2d, J=8.2 Hz, 1H); 7.29-7.38(m, 5H); 8.98 (2s, 1H); 9.11 (2s, 1H)

¹³C NMR (DMSO, 100 MHz): (hindrance of rotation) 30.9 & 31.4, 31.5 &31.9, 34.1 & 34.4, 42.9, 45.2, 71.1, 102.4, 105.9, 121.8, 126.3, 126.4,126.9, 127.5, 128.1, 128.3, 128.4, 128.9, 140.5, 155.1, 156.1, 170.0.

EXAMPLE 48(S)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone

In a manner analogous to Example 26, but using (S)-hydroxyphenylaceticacid,(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanoneis obtained.

¹H NMR (DMSO, 400 MHz): (hindrance of rotation) 0.6 (m, 0.5H); 1.30-1.70(m, 3.5H); 2.5-3 (m, 2H); 4.0 (m, 1H); 4.51 (m, 1H); 5.37-5.57 (m, 2H);6.07 (m, 1H); 6.24 (m, 1H); 6.48 & 6.72 (2d, J=8.2 Hz, 1H); 7.29-7.38(m, 5H); 8.98 (2s, 1H); 9.11 (2s, 1H)

¹³C NMR (DMSO, 100 MHz): (hindrance of rotation) 30.9 & 31.4, 31.5 &31.9, 34.1 & 34.4, 42.9, 45.2, 71.1, 102.4, 105.9, 121.8, 126.3, 126.4,126.9, 127.5, 128.1, 128.3, 128.4, 128.9, 140.5, 155.1, 156.1, 170.0.

EXAMPLE 49(R)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-one

In a manner analogous to Example 26, but using(R)-2-hydroxy-3-phenylpropionic acid,(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-oneis obtained.

¹H NMR (DMSO, 400 MHz): (hindrance of rotation) 1.04-1.70 (m, 4H);2.50-3.34 (m, 5H); 4.02 (m, 1H); 4.52 (m, 2H); 4.97 (m, 1H); 6.14 (d,J=8.2 Hz, 1H); 6.25 (m, 1H); 6.67 & 6.782 (2d, J=8.2 Hz, 1H); 7.14-7.28(m, 5H); 8.97 (2s, 1H); 9.15 (2s, 1H).

¹³C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6 & 31.7, 34.5 &34.7, 40.3 & 40.6, 42.5, 45.6, 68.6 & 68.9, 102.5, 106.1, 122.1, 126.1,126.8, 128.1, 129.6, 138.1 & 138.4, 155.3, 156.2, 171.0.

EXAMPLE 50(S)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-one

In a manner analogous to Example 26, but using(S)-2-hydroxy-3-phenylpropionic acid,(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-oneis obtained.

¹H NMR (DMSO, 400 MHz): (hindrance of rotation) 1.04-1.70 (m, 4H);2.50-3.34 (m, 5H); 4.02 (m, 1H); 4.52 (m, 2H); 4.97 (m, 1H); 6.14 (d,J=8.2 Hz, 1H); 6.25 (m, 1H); 6.67 & 6.782 (2d, J=8.2 Hz, 1H); 7.14-7.28(m, 5H); 8.97 (2s, 1H); 9.15 (2s, 1H).

¹³C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6 & 31.7, 34.5 &34.7, 40.3 & 40.6, 42.5, 45.6, 68.6 & 68.9, 102.5, 106.1, 122.1, 126.1,126.8, 128.1, 129.6, 138.1 & 138.4, 155.3, 156.2, 171.0.

EXAMPLE 51 Tyrosinase activity inhibition assay

The activity of the inhibitors is measured using a lysate of B16F1 cells(murine melanoma line). In the presence of the L-tyrosine substrate, thetyrosinase present in these cells catalyses the hydroxylation ofL-tyrosine to give L-DOPA and then the oxidation of the L-DOPA to givedopaquinone. In the presence of MBTH (3-methyl-2-benzothiazolinonehydrazone), the dopaquinone is trapped so as to form a pink complexwhich absorbs at 520 nm.

The B16F1 cells are cultured in DMEM medium+10% foetal calf serum+10⁻⁹ Mα-MSH for 4 days at 37° C. under 7% CO₂. They are treated with trypsin,washed in PBS, counted and pelleted. The pellet is taken up at 10⁷cells/mL in lysis buffer (10 mM sodium phosphate, pH 6.8 —1% Igepal) andthe suspension is treated with ultrasound for 10 seconds. Aftercentrifugation for 30 minutes at 4000 rpm, the supernatant obtainedconstitutes the cell lysate used as tyrosinase source in the enzymaticassay.

The assays are carried out in duplicate in 384-well plates in a totalvolume of 50 μl. Each well contains:

-   -   40 μl of solution containing 1.25 mM L-tyrosine, 6.25 μM L-DOPA        (cofactor) and 3.75 mM MBTH in buffer B (62.25 mM sodium        phosphate, pH 6.8—2.5% dimethylformamide),    -   5 μl of inhibitor diluted in DMSO,    -   5 μl of cell lysate diluted to ½ in 50 mM Tris HCl buffer, pH        7.5.

The plate is incubated at 37° C. and a spectrophotometric reading iscarried out at 520 nm after 6 hours of incubation. In order to avoid anypossible absorption of the products, the system uses correctedabsorbance (absorbance at time 6 h—absorbance at time zero).

The inhibitors are assayed in terms of dose-response so as to calculatean IC₅₀ (dose which inhibits 50% of the enzymatic activity).

Several internal controls are added to each experiment:

-   -   control for 100% activity: the 5 μl of inhibitor are replaced        with 5 μl of DMSO,    -   control for 50% activity: the 5 μl of inhibitor are replaced        with 5 μl of phenylthiourea at 300 μM in DMSO,    -   control for 0% activity: the L-tyrosine substrate is replaced        with buffer B.

The results obtained for the compounds of the invention are shown inTable A:

TABLE A Tyrosine hydroxylase/ Dopa oxidase IC₅₀ Name Structure (μM)4-Butylresorcinol (Rucinol)

3 Compound 48

0.2 Compound 24

0.15

EXAMPLE 52 Melanogenesis Inhibition assay

The inhibition of melanogenesis is measured in MNT1 human melanoma cellsaccording to a protocol adapted from Reigner et al., Cell Mol Biol(1999) 45: 969-980. The assay is based on the concomitant incorporationof 2 radiolabelled tracers: ¹⁴C-thiouracil is incorporated into theneosynthesized melanin and reflects melanogenesis, whereas ³H-leucine isincorporated into the proteins and reflects cell viability and,consequently, the toxicity of the compounds tested.

The MNT1 cells are seeded into 96-well plates in the presence of thetest compounds and of the radioisotopes. After incubation for 24 h at37° C., the cells are washed and the amount of the 2 radioisotopes ismeasured. The test compounds are evaluated in terms of dose-response soas to calculate an IC₅₀ for inhibition of melanogenesis on the basis ofthe ¹⁴C incorporation which is standardized through the ³Hincorporation. An IC₅₀ for cell toxicity is also calculated on the basisof the ³H incorporation.

This assay therefore makes it possible to distinguish the products thatspecifically inhibit melanogenesis from those which are cytotoxic tomelanocytes.

IC₅₀ IC₅₀ Name Formula melanogenesis toxicity 4-Butyl- resorcinol(Rucinol)

 15 μM    55 μM Compound 48

0.7 μM >999 μM Compound 24

0.3 μM >999 μM

EXAMPLE 53 Formulations

This example illustrates various formulations based on the compoundsaccording to the invention.

Topically

(a) Ointment Compound 16 0.020 g Isopropyl myristate 81.700 g Liquidpetroleum jelly 9.100 g Silica (Aerosil 200) 9.180 g (b) OintmentCompound 6 0.300 g White petroleum jelly, qs 100 g pharmaceutical grade(c) Nonionic water-in-oil cream Compound 16 0.100 g Mixture of emulsivelanolin alcohols, of 39.900 g waxes and of oils (Anhydrous eucerin)Methyl para-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 gSterile demineralized water qs 100 g (d) Lotion Compound 6 0.100 gPolyethylene glycol (PEG 400) 69.900 g 95% ethanol 30.000 g (e)Hydrophobic ointment Compound 22 0.300 g Isopropyl myristate 36.400 gSilicone oil (Rhodorsil 47 V 300) 36.400 g Beeswax 13.600 g Silicone oil(Abil 300,000 cst) qs 100 g (f) Nonionic oil-in-water cream Compound 41.000 g Cetyl alcohol 4.000 g Glyceryl monostearate 2.500 g PEG 50stearate 2.500 g Shea butter 9.200 g Propylene glycol 2.000 g Methylpara-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Steriledemineralized water qs 100 g

1. A pharmaceutical or cosmetic composition comprising a compound offormula (I) below:

in which: R1 represents: a C₁-C₅ alkyl radical, a C₃-C₆ cycloalkylradical, an aryl radical, a substituted aryl radical, an aralkylradical, a C₁-C₅ alkoxy radical, an amino radical corresponding tostructure (a):

in which R2 represents: a hydrogen, a C₁-C₅ alkyl radical, a C₃-C₆cycloalkyl radical, an aryl radical, a substituted aryl radical, apyridyl radical, an aralkyl radical, a radical corresponding tostructure (b):

in which p can have the value 1 or 2, a radical corresponding tostructure (c):

in which R4 represents: a carboxymethyl —COOCH₃ or carboxyethyl —COOEtradical, a C₁-C₃ alkyl radical, a hydrogen, and R5 represents: asubstituted or unsubstituted aryl radical, a C₃-C₆ cycloalkyl radical, apyridyl, and R3 represents: a hydrogen, a C₁-C₅ alkyl radical; or R1 mayalso represent a radical corresponding to formula (d):

in which R6 represents: a hydrogen, a C₁-C₅ alkyl radical, a C₃-C₆cycloalkyl radical, an aryl radical, a substituted aryl radical, apyridyl radical, an aralkyl radical, R7 represents: a hydrogen, a C₁-C₅alkyl radical, and R8 represents: a hydrogen, a hydroxyl, an aminoradical, a C₁-C₃ alkoxy radical; Y represents a hydrogen or a fluorine,and m and n can have the value 0, 1 or 2, or a salt of a compound offormula (I), or an enantiomer form thereof; and a pharmaceuticallyacceptable or cosmetically acceptable carrier. 2.-23. (canceled)